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Reproductive dysfunction

Robert J Norman, Warren J Kidson, Ross C Cuneo and Margaret R Zacharin
Med J Aust 2001; 174 (11): 580-583.
Published online: 23 May 2001

Position Statement

Metformin and intervention in polycystic ovary syndrome

Robert J Norman, Warren J Kidson, Ross C Cuneo, Margaret R Zacharin
on behalf of the Endocrine Society of Australia, the Australian Diabetes Society and the Australasian Paediatric Endocrine Group

MJA 2001; 174: 580-583
For editorial comment, see Lobo

Abstract - PCOS and insulin resistance - Metformin - Published studies on metformin in PCOS - What should doctors do? - References - Authors' details
- - More articles on Endocrinology


Abstract

  • Polycystic ovary syndrome (PCOS) is classically characterised by ovarian dysfunction (oligomenorrhoea, anovulation and infertility), androgen excess (hirsutism and acne), obesity, and morphological abnormalities of the ovaries (cystic enlargement and stromal expansion).
  • More recently, insulin resistance has been found to be common in PCOS, along with an increased prevalence of other features of the "metabolic syndrome", namely glucose intolerance, type 2 diabetes mellitus, and hyperlipidaemia.
  • Hyperinsulinaemia is likely to contribute to the disordered ovarian function and androgen excess of PCOS.
  • Reducing insulin resistance by lifestyle modifications such as diet and exercise improves endocrine and menstrual function in PCOS. These lifestyle modifications are the best initial means of improving insulin resistance.
  • Metformin, an oral hypoglycaemic agent that increases insulin sensitivity, has been shown to reduce serum concentrations of insulin and androgens, to reduce hirsutism, and to improve ovulation rates. The effect of metformin alone on fertility rates is unknown. Some studies suggest that metformin will reduce total body weight to a small extent, but with a predominant effect on visceral adipose reduction.
  • The effects of metformin on lipid abnormalities, hypertension or premature vascular disease are unknown, but the relative safety, moderate cost, and efficacy in reducing insulin resistance suggest that metformin may prove to be of benefit in combating these components of the "metabolic" syndrome in PCOS. Further properly planned randomised controlled trials are required.

The definition of polycystic ovary syndrome (PCOS) is controversial and subject to different interpretations. The typical presentation (see Box 1) is with the clinical triad of obesity, androgen excess (hirsutism and acne), and menstrual irregularity (oligomenorrhoea, secondary amenorrhoea, and related infertility). Patients may present with individual components of the syndrome. For example, obese patients may simply present with menstrual irregularity. Biochemical investigation usually shows mild to moderate androgen excess (elevated total and free testosterone, suppressed sex-hormone-binding globulin, and increased adrenal and ovarian androgens). On ultrasonography, ovarian morphology typically shows multiple cysts, increased stroma and enlarged volume, although a normal appearance on ultrasound does not exclude the diagnosis. There is considerable phenotypic variability in the presentation, with not all patients expressing all of these abnormalities. Lean individuals may have PCOS.

As there is some phenotypic overlap between patients with congenital adrenal hyperplasia or Cushing's syndrome and those with PCOS, the work-up should include consideration of these differential diagnoses. The prevalence of PCOS in premenopausal women is said to be 6%-10%.1



PCOS and insulin resistance

Hyperinsulinaemia, insulin resistance and impaired glucose tolerance are very common in women with PCOS, particularly in those with a body mass index (BMI) greater than 30,2,3 but insulin resistance may occur in all women with PCOS, even those who are lean. Early-onset type 2 (non-insulin-dependent) diabetes mellitus is a prominent feature of PCOS in long-term follow-up studies. Insulin resistance is largely the result of reduced insulin action in peripheral, non-hepatic tissues such as skeletal muscle. In some cases the insulin resistance is thought to be caused by genetic disorders of insulin-independent serine phosphorylation of the Β-subunit of the insulin receptor.1 Insulin resistance does not improve with suppression of ovarian androgens, but responds to diet and exercise, as in type 2 diabetes mellitus.

However, in women with PCOS the ovary does not appear to be resistant to insulin when studied in vitro. Insulin action in the ovary is mediated via the insulin receptor rather than the type 1 insulin-like growth factor (IGF) receptor, which binds IGF-I with high affinity and insulin with low affinity. Insulin increases ovarian androgen production and may thereby impair ovulation,4 suggesting that hyperinsulinaemia may be pathogenetically important in PCOS.

Strategies that reduce insulin resistance, such as weight loss, diet and exercise, have been shown to improve hyperinsulinaemia, menstrual abnormalities, and ovulation rates.5 This forms the basis for the potential use of metformin to treat the raised androgen concentrations and menstrual disturbances in PCOS (see Box 2). There is also emerging support for the use of other insulin-sensitising agents, such as thiazolidenediones,6 but that is beyond the scope of this review.


Metformins

Metformin is a biguanide drug whose mechanism of action is poorly understood, but it is known to enhance the peripheral action of insulin without stimulating insulin secretion. The drug is widely used in type 2 diabetes mellitus. Metformin is claimed to have a multifactorial action, with prime effects on insulin sensitivity in both the liver (where it reduces basal hepatic glucose production) and in peripheral tissues (where it increases glucose uptake into muscle in the insulin-stimulated state after meals). It reduces blood glucose concentrations without causing hypoglycaemia (except when used with alcohol). Other than in diabetes, metformin has been used to improve insulin sensitivity in first-degree relatives of people with diabetes, and people with upper-body obesity and hypertension. The usual antidiabetic oral dose is 500-2500 mg daily.



Published studies on metformin in PCOS

A Medline search between 1966 and July 1999, covering the keywords "polycystic ovary syndrome", "metformin", and "insulin sensitizing drugs", identified 14 published original studies containing primary data on the use of metformin in PCOS.7-20 Most of these were observational studies, in which metformin was administered to women with PCOS, with recording of biochemical and clinical effects before and during treatment. The end-points studied varied from glucose tolerance and insulin resistance to effects on ovulation and pregnancy. Almost all studies were of short duration (4-6 months at most); the clinical effects of metformin may take longer to be fully manifest.

The non-randomised studies found:

Effects on fasting insulin levels and insulin resistance in PCOS: Most studies claim some reduction in fasting and glucose-stimulated insulin levels as well as improvements in insulin sensitivity. However, others fail to confirm these observations. There is no apparent explanation on the basis of doses used, but the degree of obesity is important in the response.

Effects on androgens and sex-hormone-binding globulin: Most studies show beneficial effects on free testosterone and sex-hormone-binding globulin levels. However, this is not supported by other studies which are similar in design.

Effects on menstruation, ovulation and pregnancy: Most publications do not deal with clinical outcomes. Those that do indicate improvement in spontaneous menstruation in 20%-50% of women. Some women became pregnant.

There were only five randomised trials comparing metformin with placebo in PCOS to July 1999.7-10,18 A single-blind crossover study showed no difference in insulin resistance between the placebo and metformin arms of the trial after treatment.7 Another study was unable to show any benefit of metformin over placebo when both were used in combination with diet.8 Neither of these two studies addressed clinical reproductive outcomes. Of the remaining randomised trials, two dealt with hormonal outcomes in obese and non-obese women with PCOS, and showed an improvement in insulin secretion, luteinising-hormone- stimulated 17-hydroxyprogesterone secretion, decreased levels of luteinising hormone and free testosterone, and an increased level of sex-hormone-binding globulin with metformin therapy.9,18 The third looked at the effects of metformin with or without clomiphene citrate on ovulation.10 Sixty-one women with PCOS were randomly allocated to treatment with metformin or placebo, with 34% and 4%, respectively, ovulating after taking 1500 mg daily of metformin or placebo. Of those who did not ovulate, 90% in the metformin group responded to the addition of clomiphene citrate, compared with only 4% in the placebo group. Pregnancy was not an outcome measure in this study and few of the other studies reported pregnancies.

During the preparation of this review (through to January 2001), we became aware of an additional 12 interventional (but not placebo-controlled) studies of metformin in PCOS;21-31 these studies reinforce the conclusions above. One important study randomly allocated women to therapy with metformin or conventional therapy for normalising menstrual activity and reducing androgen excess (ethinyl oestradiol plus cyproterone acetate).30 This study showed reductions in body weight, insulin levels and androgens with metformin, but an increase in glucose intolerance with the conventional therapy.

Two important randomised, double-blind, placebo-controlled trials of metformin therapy in women with PCOS have recently been published.32,33 In one, 23 women with PCOS randomly allocated to treatment with either placebo or metformin (500 mg three times daily) for six months showed significant benefits in menstrual pattern, ovulation rate, insulin sensitivity, serum free testosterone levels, and gonadotropin-releasing-hormone-stimulated 17-hydroxyprogesterone levels without changes in body weight.32 Almost 50% of the women involved developed ovulatory cycles during an open-label, long-term extension of the study. In the other, 20 women with obesity and PCOS and 20 with obesity only were randomly assigned to either placebo or metformin therapy (850 mg twice daily) for six months. Metformin reduced visceral fat mass and improved glucose-stimulated insulin levels, hirsutism and menstrual pattern in those with PCOS. Two studies now show that metformin decreases hirsutism.30,33



What should doctors do?

The management of women with PCOS should go beyond therapy for hirsutism and acne, menstrual irregularity and infertility. Currently, it seems justified to screen all women with PCOS for glucose intolerance or diabetes mellitus (with oral glucose tolerance testing) and conventional cardiovascular risk factors (smoking, blood pressure, hyperlipidaemia), and to institute lifestyle modifications as necessary.

The literature supports a trial of metformin in patients with anovulation, androgen excess and vascular risk factors, as these abnormalities may be reduced. However, the long-term effects of treatment with metformin on vascular risk factors, morbidity and mortality are unknown. Clinically relevant end-points to follow may include fasting serum glucose levels (with or without tests for oral glucose tolerance and fasting plasma insulin level), fasting serum levels of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, blood pressure, serum testosterone level and hirsutism and acne, and menstrual pattern and fertility. Side effects of metformin (which include diarrhoea and vitamin B12 malabsorption) may limit compliance in some patients. Lactic acidosis is a rare but serious side effect in diabetes, but has not been described in PCOS.

Given the present lack of long-term safety data and demonstrable efficacy in a large number of patients, we recommend that metformin use be supervised by an endocrinologist or physician with expertise in the area. Ideally, further research should be encouraged so that outcomes can be scrutinised and regulatory issues can be carefully addressed.

A summary of recommendations for the use of metformin in PCOS is shown in Box 3.

 

Background and evidence basis of recommendations

This article was commissioned by the Endocrine Society of Australia, the Australian Diabetes Society and the Australasian Paediatric Endocrine Group to review current published evidence about the efficacy of the use of metformin in treating the polycystic ovary syndrome in women. It was prepared by Robert J Norman, Warren J Kidson, Ross C Cuneo and Margaret R Zacharin, and circulated to the Councils of the above societies for consultation and suggested modifications.

 

References

  1. Lobo RA, Carmina E. The importance of diagnosing the polycystic ovary syndrome. Ann Intern Med 2000; 132: 989-993.
  2. Ehrmann E, Cavaghan M, Barnes R, et al. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care 1999; 22: 141-146.
  3. Legro R, Kunselman A, Dodson W, et al. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab 1999; 84: 165-169.
  4. Nestler JE, Jakubowicz DJ, de-Vargas AF, et al. Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. J Clin Endocrinol Metab 1998; 83(6): 2001-2005.
  5. Huber-Buchholz MM, Carey DG, Norman RJ. Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone. J Clin Endocrinol Metab 1999; 84: 1470-1474.
  6. Ehrmann DA, Schneider DJ, Sobel BE, et al. Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1997; 82: 2108-2116.
  7. Acbay O, Gundogdu S. Can metformin reduce insulin resistance in polycystic ovary syndrome? Fertil Steril 1996; 65: 946-949.
  8. Crave JC, Fimbel S, Lejeune H, et al. Effects of diet and metformin administration on sex hormone-binding globulin, androgens, and insulin in hirsute and obese women. J Clin Endocrinol Metab 1995; 80: 2057-2062.
  9. Nestler JE, Jakubowicz DJ. Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17 alpha activity and serum androgens. J Clin Endocrinol Metab 1997; 82: 4075-4079.
  10. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med 1998; 338: 1876-1880.
  11. Diamanti-Kandarakis E, Kouli C, Tsianateli T, Bergiele A. Therapeutic effects of metformin on insulin resistance and hyperandrogenism in polycystic ovary syndrome. Eur J Endocrinol 1998; 138: 269-274.
  12. Ehrmann DA, Cavaghan MA, Imperial J, et al. Effects of metformin on insulin secretion, insulin action, and ovarian steroidogenesis in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1997; 82: 524-530.
  13. Morin Papunen LC, Koivunen RM, Tomas C, et al. Decreased serum leptin concentrations during metformin therapy in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab 1998; 83: 2566-2568.
  14. Morin Papunen LC, Koivunen RM, et al. Metformin therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome. Fertil Steril 1998; 69: 691-696.
  15. Sir T, Castillo T, Munoz S, et al. [Effects of metformin on insulin resistance in obese and hyperandrogenic women]. Rev Med Chil 1997; 125: 1457-1463.
  16. Velazquez EM, Mendoza S, Hamer T, et al. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metab Clin Exp 1994; 43: 647-654.
  17. Velazquez E, Acosta A, Mendoza SG. Menstrual cyclicity after metformin therapy in polycystic ovary syndrome. Obstet Gynecol 1997; 90: 392-395.
  18. Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med 1996; 335: 617-623.
  19. Velazquez EM, Mendoza SG, Wang P, Glueck CJ. Metformin therapy is associated with a decrease in plasma plasminogen activator inhibitor-1, lipoprotein(a), and immunoreactive insulin levels in patients with the polycystic ovary syndrome. Metabolism 1997; 46: 454-457.
  20. Zarate A, Hernandez M, Fonseca E, Ochoa RM. [Use of metformin to treat adolescents with polycystic ovarian syndrome] Empleo de metformin en manejo de adolescentes con el sindrome de ovarios poliquisticos. Ginecol Obstet Mex 1997; 65: 504-507.
  21. Morin-Papunen LC, Koivunen RM, Tomas C, et al. Decreased serum leptin concentrations during metformin therapy in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab 1998; 83: 2566-2568.
  22. Unluhizarci K, Kelestimur F, Sahin Y, Bayram F. The treatment of insulin resistance does not improve adrenal cytochrome P450c17 alpha enzyme dysregulation in polycystic ovary syndrome. Eur J Endocrinol 1999; 140: 56-61.
  23. Glueck CJ, Wang P, Fontaine R, et al. Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with polycystic ovary syndrome. Metabolism 1999; 48: 511-519.
  24. De-Leo V, La-Marca A, Ditto A, et al. Effects of metformin on gonadotropin-induced ovulation in women with polycystic ovary syndrome. Fertil Steril 1999; 72: 282-285.
  25. La-Marca A, Morgante G, Paglia T, et al. Effects of metformin on adrenal steroidogenesis in women with polycystic ovary syndrome. Fertil Steril 1999; 72: 985-989.
  26. La-Marca A, Egbe TO, Morgante G, et al. Metformin treatment reduces ovarian cytochrome P-450c17alpha response to human chorionic gonadotrophin in women with polycystic ovary syndrome. Human Reprod 2000; 15: 21-23.
  27. De-Leo V, La-Marca A, Orvieto R, Morgante G. Effects of metformin on insulin-like growth factor (IGF) I and IGF-binding protein I (IGFBP-I) in polycystic ovary syndrome. J Clin Endocrinol Metab 2000; 85: 1598-1600.
  28. Unluhizarci K, Kelestimur F, Bayram F, et al. The effects of metformin on insulin resistance and ovarian steroidogenesis in women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 1999; 51: 231-236.
  29. Wang A, Li M, Lu C. Role of hyperinsulinemia in pathogenesis of polycystic ovary syndrome. Chung Hua Fu Chan Ko Tsa Chih 1998; 33: 731-734.
  30. Kolodziejczyk B, Duleba AJ, Spaczynski RZ, Pawelczyk L. Metformin therapy decreases hyperandrogenism and hyperinsulinemia in women with polycystic ovary syndrome. Fertil Steril 2000; 73: 1149-1154.
  31. Morin-Papunen LC, Vauhkonen I, Koivunen RM, et al. Endocrine and metabolic effects of metformin versus ethinyl estradiol-cyproterone acetate in obese women with polycystic ovary syndrome: a randomised study. J Clin Endocrinol Metab 2000; 85: 3161-3168.
  32. Moghetti P, Castello R, Negri C, et al. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomised, double-blind, placebo-controlled 6 month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metab 2000; 85: 139-146.
  33. Pasquali R, Gambineri A, Biscotti D, et al. Effects of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without polycystic ovary syndrome. J Clin Endocrinol Metab 2000; 85: 2767-2774.



Authors' details

Department of Obstetrics and Gynaecology, University of Adelaide, Adelaide, SA.
Robert J Norman, FRANZCOG, FRCPA, Professor.

Prince of Wales Hospital, Randwick, and the Children's Hospital, Sydney, NSW.
Warren J Kidson, MB BS, FRACP, Visiting Medical Officer; and Visiting Endocrinologist, Royal Hospital for Women, Paddington, NSW.

Metabolic Research Unit, Department of Medicine, University of Queensland, and Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Brisbane, QLD.
Ross C Cuneo, FRACP, PhD, Endocrinologist.

Department of Endocrinology and Paediatrics, The Royal Children's Hospital, Melbourne, VIC.
Margaret R Zacharin, MB BS, FRACP, Endocrinologist.

Reprints will not be available from the authors.
Correspondence: Associate Professor R C Cuneo, Department of Medicine, Princess Alexandra Hospital, Brisbane, QLD 4102.

©MJA 2001
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1: Clinical presentations of patients with polycystic ovary syndrome

Reproductive dysfunction

  •  Oligomenorrhoea and anovulation
  •  Infertility
  •  Endometrial cancer

Androgen excess

  •  Acne and hirsutism

Obesity and metabolic disorders

  •  Insulin resistance
  •  Increased prevalence of type 2 diabetes mellitus
  •  Increased levels of total and low-density lipoprotein cholesterol
  •  Decreased level of high-density lipoprotein cholesterol
  •  Impaired fibrinolysis
  •  Hypertension
  •  Increased prevalence of vascular disease and possibly mortality
Back to text
 

2: Potential strategies to prevent or treat metabolic derangements in polycystic ovary syndrome

  •  Weight reduction and exercise
  •  Screening for and treatment of conventional vascular risk factors
    • Glucose intolerance and diabetes mellitus
    • Hyperlipidaemia
    • Hypertension
  • Primary treatment of insulin resistance
    • Metformin
    • Thiazolidenediones
Back to text
 

3: Summary of recommendations for the use of metformin in polycystic ovary syndrome (PCOS)

Obese patients
Many of the benefits claimed for metformin can be obtained by lifestyle modification. This should be the first-line approach to overweight anovulatory women with PCOS.

Infertile or oligomenorrhoeic patients
Metformin may benefit some women who have anovulatory PCOS. Daily doses up to 2000 mg may improve the menstrual cycle, with the resumption of ovulation, but an increase in pregnancy rates is not proven. Metformin in combination with moderate doses of clomiphene citrate (50-100 mg) may improve ovulation rates and is a cheaper option than the use of gonadotropins.

Hirsute patients
The value of metformin in reducing hyperandrogenaemia is small but detectable. The findings of one controlled, long-term study support the use of metformin in this situation.

Patients with the "metabolic" syndrome
Long-term use of metformin to reduce the sequelae of insulin resistance in PCOS (hypertension, hyperlipidaemia, and premature vascular disease) is untested but needs to be explored given the value of metformin in type 2 diabetes mellitus.

Potential side effects
While gastrointestinal side effects may reduce long-term compliance in some patients, there are no known severe side effects of metformin in patients with PCOS.

More research needed
There is an urgent need for more clinical trials before widespread use of metformin in PCOS is accepted.

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  • Robert J Norman
  • Warren J Kidson
  • Ross C Cuneo
  • Margaret R Zacharin


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